Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
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DOI：
10.1371/journal.pone.0022374
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Schwartz M
中科院分区：
文献类型：
--
作者：
Finkelstein A;Kunis G;Seksenyan A;Ronen A;Berkutzki T;Azoulay D;Koronyo-Hamaoui M;Schwartz M
肌萎缩侧索硬化症（ALS）是一种以脊髓运动神经元（MN）的选择性死亡为特征的快速进展的致命性神经退行性疾病，并且与局部神经炎症相关。循环CD 4 + T细胞是控制神经退行性疾病中的局部有害炎症和支持神经元存活（包括MN）所必需的。T细胞缺乏增加神经元的损失，而提高T细胞水平降低it. There，我们表明，在突变型超氧化物歧化酶1 G93 A（mSOD 1）小鼠模型的ALS，自然杀伤T（NKT）细胞的水平显着增加，和T细胞的分布都改变了淋巴器官和脊髓相对于野生型小鼠。在肝脏中观察到NKT细胞的最显著升高，伴随器官萎缩。肝脏胰岛素样生长因子（IGF）-1的表达水平下降，而IGF结合蛋白（IGFBP）-1的表达增加了20倍以上的mSOD 1小鼠相对于野生型动物。此外，当用NKT配体离体刺激时，发现症状前mSOD 1小鼠的肝淋巴细胞分泌显著更高水平的细胞因子。在特定方案中，使用α-半乳糖神经酰胺（α-GalCer）类似物对NKT细胞进行免疫调节，减少了外周中这些细胞的数量，并诱导T细胞募集到受影响的脊髓中，导致mSOD 1小鼠的寿命适度但显著延长。这些结果将NKT细胞确定为ALS的潜在参与者，并且将肝脏确定为该疾病的主要病理学的额外部位，从而强调ALS不仅是非细胞自主性疾病，而且也是非组织自主性疾病。此外，研究结果表明，除了基于MN的神经保护和旨在减少氧化应激的全身治疗外，还存在潜在的新治疗靶点，如肝脏，用于免疫调节干预以改善疾病。
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4+ T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.
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DOI：
10.4049/jimmunol.181.7.4791
发表时间：
2008-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Grajewski RS;Hansen AM;Agarwal RK;Kronenberg M;Sidobre S;Su SB;Silver PB;Tsuji M;Franck RW;Lawton AP;Chan CC;Caspi RR
通讯作者：
Caspi RR
影响因子：
4.4
作者：
Bakalash, S;Kessler, A;Schwartz, M
通讯作者：
Schwartz, M
影响因子：
4.2
作者：
DAWSON, G;STEFANSSON, K
通讯作者：
STEFANSSON, K
DOI：
10.1073/pnas.0402026101
发表时间：
2004-07-27
影响因子：
11.1
作者：
Dupuis, L;Oudart, H;Loeffler, JP
通讯作者：
Loeffler, JP
DOI：
10.1073/pnas.0807419105
发表时间：
2008-10-07
影响因子：
11.1
作者：
Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
通讯作者：
Appel, Stanley H.